The long-range of this project is to develop novel therapeutic strategies that ameliorate muscle atrophy and accelerate muscle rehabilitation following pathological conditions such as spinal cord injury. This application is consistent with the vision of the Christopher and Dana Reeve Paralysis Act (CDRPA) which promotes the interaction of scientists conducting similar work to further enhance understanding and expedite the search for effective treatment interventions for millions of Americans living with paralysis. "The CDRPA encourages coordination of research to prevent redundancies and hopefully hasten discovery of better treatments and Page 1 cures and, as importantly, to improve the daily lives today for those living with paralysis". The proposed application presents a unique collaboration between a group of productive scientists with diverse, yet complimentary expertise and a common interest in the recovery of muscle and motor function. This team of national experts explores a new area of research focusing on complimentary treatment strategies utilizing pharmacological/molecular therapies modulating muscle growth in conjunction with emerging rehabilitation interventions. The specific objectives of this 2 year application are: 1) To identify novel pharmacological strategies to ameliorate muscle atrophy induced by disuse/unloading and promote muscle recovery;2) To validate a new animal model of incomplete spinal cord injury for the assessment of rehabilitation strategies. This Project will provide important preclinical data in an area of rapid pharmacological development and will set the stage for a more clinical relevant model of spinal cord injury. The drugs that are targeted are either approved for human use or they are in clinical development and will allow rapid translation to animal models. This proposal provides some unique opportunities and presents an important step forward in the translation towards human trials. The results of the individual studies will also make important new contributions to the science base of muscle rehabilitation and spinal cord injury. The objectives of this synergistic program will be addressed in the following three projects: Project I: Attenuation of Skeletal Muscle Atrophy and Loss of Muscle Function. This project will evaluate existing drugs, with the therapeutic goal of ameliorating muscle atrophy induced by disuse/unloading. Specifically, this project will assess the efficacy of inhibition of proteolysis in the prevention of muscle atrophy and determine its impact on muscle growth upon reloading (collaboration with Project 2 and Cores A, B and C). PI: H. Lee Sweeney - [The scope of Aim 1 had been reduced and Aim 2 has been removed]. Project II: Promoting Muscle Regeneration and Rehabilitation by Insulin-like Growth Factor-I. This project will investigate the potential of systemic and local dellivery of insulin-like growth factor I (IGF-I) to promote muscle regeneration and hypertrophy following disuse/unloading after hindlimb suspension and cast immobilization (collaboration with Project 1, and Cores A, B, and C). PI: Elisabeth Barton - [Aims 1 &2 are reduced and Aim 3 has been removed]. Project III: Locomotor Training to Promote Muscle Rehabilitation following Spinal Cord Injury. This project will validate a new animal model of incomplete SCI to faciliate future studies targeting the development of more effective rehabilitation strategies. The availability of a reliable SCI animal model that more closely mimics the clinical situation would present a significant advance in the field of SCI research. Subsequently, this project will evaluate the feasibility and efficacy of implementing activity based rehabilitation interventions, such as locomotor treadmill training, in this new animal model. [Aims 2-4 have been removed and Aim 1 has been expanded to include validation of a new SCI model before evaluating the effect of the treadmill locomotor training intervention]. To optimize the economy of the program three centralized cores will continue to support all three projects. The cores will consist of an Administrative and Data Management Core (A), a Spinal Cord Injury and Physiological Assessment Core (B), and a Magnetic Resonance Imaging Core (C). The program is distributed across the two sites: the University of Florida and the University of Pennsylvania. The program builds on the unique, complementary expertise at both sites and a long history of productive collaboration.